title: Kearns-Sayre syndrome caused by defective R1/p53R2 assembly.
abstract: BACKGROUND
  Mutations in RRM2B encoding ribonucleotide reductase (RNR) p53R2 subunit usually cause paediatric-onset mitochondrial disease associated with mitochondrial DNA (mtDNA) depletion. The importance of RNR dysfunction in adult mitochondrial disease is unclear.
  
  
  OBJECTIVE
  To report the RRM2B mutation frequency in adults with multiple mtDNA deletions and examine RNR assembly in a patient with Kearns-Sayre syndrome (KSS) caused by two novel RRM2B mutations.
  
  
  METHODS
  50 adult patients with multiple mtDNA deletions in skeletal muscle were studied. DNA sequencing of RRM2B was performed in patients without mutations in mtDNA maintenance genes POLG and C10orf2. RNR protein was studied using western blot and Blue-native polyacrylamide gel electrophoresis (BN-PAGE).
  
  
  RESULTS
  Four per cent (two unrelated cases) of this adult cohort harboured RRM2B mutations. Patient 1 had KSS and two novel missense mutations: c.122G→A; p.Arg41Gln and c.391G→A; p.Glu131Lys. BN-PAGE demonstrated reduced heterotetrameric R1/p53R2 RNR levels compared with controls, despite normal steady-state p53R2 levels on western blot, suggesting failed assembly of functional RNR as a potential disease mechanism. Patient 2 had late-onset progressive external ophthalmoplegia and fatigue. A heterozygous deletion c.253_255delGAG; p.Glu85del was identified. Muscle histology in both cases showed significant numbers of necrotic muscle fibres, possibly indicating enhanced apoptotic cell death.
  
  
  CONCLUSIONS
  These data indicate that 4% of adult mitochondrial disease with multiple deletions is caused by RNR dysfunction. KSS has not previously been linked to a nuclear gene defect. Evidence that disease pathogenesis may be caused by defective RNR assembly is given. RRM2B screening should be considered early in the differential diagnosis of adults with multiple mtDNA deletions.
authors.affiliation: 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.forename: Elisa
authors.initials: E
authors.lastname: Fassone
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.forename: Michael
authors.initials: M
authors.lastname: Sadowski
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.forename: Ese E
authors.initials: EE
authors.lastname: Mudanohwo
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Woodward
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000235:genetics*; D009154:Mutation; D012264:Ribonucleotide Reductases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases